Toxicity spirolide

There are several groups of spirolides. By far the most toxic is desmethyl spirolide C. Its LD50 value is 5-8 [tg/kg by the i.p. route. Via gavage, its LD50 is about 160 [tg/kg and for exposure via the feed it is about 500 [tg/kg in fasted mice and 1000 [tg/kg in nonfasted mice [53], Less information is available about the other cychc imines. 

The imine function is essential for the toxicity of the cyclic imines. According to Hu et al. [56], the imine ring is easily opened at low pH or upon enzymatic hydrolysis. Since the pH in the human stomach is much lower than in mice (pH 1-3 compared with 3-5), it is speculated that spirolides may undergo hydrolysis to less toxic compounds in humans. 

Cembella, A.D. and Krock, B., Biogeography of spirolides in Alexandrium ostenfeldii from the North Atlantic—implications for shellfish toxicity and seafood safety, in 6th International Conference on Molluscan Shellfish Safety Blenheim, New Zealand, 2007. 

Data on the acute i.p. toxicity of spirolides are summarized in Table 27.3. By intraperitoneal injection, spirolides B and D are of similar toxic potential [12]. In contrast, spirolides E and F, in which the cyclic imine moiety is destroyed, are much less toxic [13]. The LD50 of a mixture of spirolides, containing predominantly 13-desmethyl spirolide C, was reported as 40 [tg/kg after intraperitoneal injection in mice [46]. The toxicides of pure samples of desmethyl spirolide C, spirolide C, and 20-methyl spirolide G were much higher, however, with LD50 values between 6.5 and 8.0 [tg/kg... 

The acute toxicity of desmethyl spirolide C by intraperitoneal injection was the same in fasted... 

Acute Toxicity of Spirolides by Intraperitoneal Injection in Mice... 

The spirolides are less toxic by oral dosing than by injection (Table 27.4). The aforementioned spirolide mixture had an LD50 of 1000 [tg/kg after dosing by gavage [46], while pure desmethyl... 

The spirolides were even less toxic when administered to mice as a mixture with food. In initial smdies, fasted mice were found to be reluctant to eat dry mouse food containing desmethyl spirolide C, but enough mice consumed the food within a reasonable period of time (<10 min) to establish an LD50. This was 625 [tg/kg [47]. Other feeding techniques were also employed in order to disguise the presence of the test substance and thereby ensure its rapid consumption by the mice. Desmethyl spirolide C was mixed into powdered mouse food ( 150 mg), which was then made into a paste by addition of water. This was rolled into a pellet and fed to a mouse that had been fasted... 

Because of the avidity of the mice for cream cheese, the spiroUdes could also be fed in this matrix to mice without the need for fasting. The acute toxicities of desmethyl spirolide C, spirolide C, and 20-methyl spirolide G were higher in fasted mice than those in fed mice by factors of between... 

Indeed, if the effects of spirolides in humans reflect those in animals, such minor effects are not to be expected, but rather paralysis and death. Pinnatoxins have been isolated from shellfish of fhe genus Pinna. Several outbreaks of poisoning have been reported in Japan and China among individuals consuming Pinna species [31,33], An association between toxicity of the shellfish and the presence of the pinnatoxins therein has not, however, been established. Indeed, the poisoning incidents were initially ascribed to contamination of the shellfish by Vibrio spp. [31]. 

Among the spirolide derivatives thathave been studied in detail (spirolide C, desmethyl spirolide C and 20-methyl spirolide G), there is little difference in acute toxicity, either by injection or by oral administration. In pinnatoxin and pteriatoxin derivatives, however, large differences in toxicity are seen among compounds of different structure. Pinnatoxins A-C and pteriatoxins A-C differ only in the nature of the substituent at position 33. hi both, compounds B and C are stereoisomers. Pinnatoxin A, which has a carboxyl group at C-33, is approximately 14 times less toxic than a mixture of pinnatoxins B and C, which have a glycine residue at this site. The situation with the pteriatoxins is even more remarkable. These compounds may be considered as derivatives of 3-(2-hydroxyethylthio)-... 

The imine function of the cyclic imines is of paramount importance for their toxicity. When the imine group is reduced, as in gymnodamine and dihydrospirolide B, or destroyed by ring-opening, as in spirolides E and F, the toxicity is greatly decreased [6,13]. Indeed, there are no data on the acute toxicity of derivatives devoid of the imine function, with no effects being reported at the highest dose levels employed (up to 4040 [tg/kg). 

Hu T. et al. Characterization of spirolides A, C, and 13-desmethyl C, new marine toxins isolated from toxic plankton and contaminated shellfish, J. Nat. Prod. 64, 308, 2001. 

Aasen J. A.B. et al. Discovery of fatty acid ester metabolites of spirolide toxins in mussels from Norway using liquid chromatography/tandem mass spectrometry. Rapid Comm. Mass Spec. 20, 1531, 2006. Gonzalez A.V. et al. First evidence of spirolides in Spanish shellfish, Toxicon 48, 1068, 2006. Uemura D. et al. Pinnatoxin A a toxic amphoteric macrocycle from the Okinawan bivalve Pimm muricata, J. Am. Chem. Soc. 117, 1155, 1995. 

The situation described could be applicable to the management of some toxins, like some cyclic imines (gymnodimine and spirolides) or toxins produced by Ostreopsis spp. (palytoxius) that have beeu reported to be fouud iu shellfish products and have demonstrated high toxicity in mice (Parts VlllDandlX). 

In the pinnatoxins and the spirolides, the imine function is binding on a seven-membered cycle. The presence of a carboxylic acid function in pinnatoxins A-D make them betaines this is not the case for spirolides A-F, all of which have several spiro cycles. Among the four pinnatoxins, B and C are the most toxic. 

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